Intramolecular Ring-Opening of Oxetanes: Access to Functionalised Hydroxymethyl 2,3-Dihydroimidazo[1,2-c]quinazolines

Abstract

An intramolecular oxetane ring-opening was developed, affording novel 2-(hydroxymethyl)-2,3-dihydroimidazo[1,2-c]quinazolines from N-(3-methyloxetan-3-yl)quinazolin-4-amines under mild conditions. The resulting medicinally relevant tricyclic scaffolds were synthesised in good yields with diverse substituents. Moreover, reaction optimisation led to the development of a one-pot procedure.

Key words

oxetane ring-opening - intramolecular cyclization - imidazoquinazolines - one-pot synthesis

• References and Notes

• 1 Kettle JG, Wilson DM. Drug Discovery Today 2016; 21: 1596
• 2 Wu P, Nielsen TE, Clausen MH. Trends Pharmacol. Sci. 2015; 36: 422
• 3 Tiwary B, Pradhan K, Nanda AK, Chakraborty R. J. Chem. Biol. Ther. 2015; 1: 104 ; DOI: 10.4172/2572-0406.1000104
• 4 Baldwin JE. J. Chem. Soc., Chem. Commun. 1976; 734
• 5 Vlasenko AF, Mandrichenko BE, Rogul’chenko GK, Sinyak RS, Mazur AI, Kochergin PM. Khim. Geterotsikl. Soedin. 1976; 6: 834
• 6 Korshin EE, Sabirova LA, Levin YA. Synthesis 2012; 44: 3512
• 7 Claudi F, Franchetti P, Grifantini M, Martelli S. J. Org. Chem. 1974; 39: 3508
• 8 Bull JA, Croft RA, Davis OA, Doran R, Morgan KF. Chem. Rev. 2016; 116: 12150
• 9 Ng FW, Lin H, Tan Q, Danishefsky SJ. Tetrahedron Lett. 2002; 43: 545
• 10 Hammet LP. J. Am. Chem. Soc. 1937; 59: 96
• 11 (2-Methyl-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methanols 4a–f; General Procedure The appropriate 4-chloroquinazoline 1 (100 mg), 3-methyloxetan-3-amine (2; 1.2 equiv), and DIPEA (2 equiv) were dissolved in MeCN (3 mL) and the solution was sealed in a microwave tube. The tube was purged with N₂ for 1 min and then heated to 150 °C for 4 h in a microwave reactor. The mixture was cooled to 25 °C then evaporated to dryness and purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5μ silica, 30 mm diameter, 100 mm long), eluting with decreasingly polar mixtures of 1% aq NH₃ and MeCN. Fractions containing the desired compound were evaporated to dryness to afford the product 4. (2-Methyl-9-nitro-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methanol (4b) Yellow solid; yield: 288 mg (93%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.24 (s, 3 H, Me), 3.36 (dd, J = 6.4, 10.9 Hz, 1 H, CH₂O), 3.44 (dd, J = 5.9, 10.9 Hz, 1 H, CH₂O), 3.77 and 4.15 (d, J = 10.9 Hz, 1 H, and d, J = 10.9 Hz, 1 H, CH₂), 5.00 (t, J = 5.9 Hz, 1 H, OH), 7.53 (d, J = 8.9 Hz, 1 H, Ar-H), 8.10 (s, 1 H, Ar-H), 8.32 (dd, J = 2.7, 8.9 Hz, 1 H, Ar-H), 8.56 (d, J = 2.7 Hz, 1 H, Ar-H). ¹³C NMR (101 MHz, DMSO-d ₆, 30 °C): δ = 24.27 (CH₃), 53.81 (CH₂), 67.66 (CH₂O), 71.42 (C), 118.57 (C), 120.54 (CH), 127.07 (CH), 127.93 (CH), 144.18 (C), 147.86 (CH), 150.12 (C), 151.49 (C). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₃N₄O₃: 261.0909; found: 261.0988, 215.1053 [M – NO₂]⁺.